Virulent serotypes of Streptococcus pneumoniae rank as the leading pathogen in childhood bacteremias, in adult pneumonias, and in life-threatening infections in the immunocompromised host. Host defense against pneumococcal infection requires the binding of C3b, the opsonic fragment of the third component of complement (C3), to the microbial surface in preparation for ingestion by phagocytic cells. In previous studies with virulent serotypes of Streptococcus pneumoniae (3,4,6A,14), we have shown how a particular biochemical structure of C3 --- the reactive thiolester bond --- directs the covalent binding of opsonic C3b to the organism by means of a transacylation reaction. We have also described serotypic differences in the amount, biochemistry (ester vs. amide) and degradation of covalently deposited C3b and have demonstrated how C3b and iC3b on the pneumococcal capsule serve as ligands for membrane complement receptor on phagocytic cells. We therefore propose to analyze, at the molecular level, the functional mechanisms directing deposition and degradation of C3b on the pneumococcal surface and the membrane receptors which, in recognizing these C3 ligands, regulate intracellular functions in phagocytosis and in antibody production. We shall first investigate the role of C3 and its active fragments in the phagocytosis of virulent Streptococcus pneumoniae. Using prototypic surfaces bearing purified C3b and iC3b with ester- or amide-modification at the thiolester site, we shall derive principles of phagocytosis which can then be applied to the study of ester-linked or amide-linked C3b and iC3b on the capsule or cell wall of genetically related pneumococci differing only in the presence or absence of capsule. Secondly, we shall examine how C3 and its active fragments may affect the production of type-specific anticapsular antibody to pneumococcal polysaccharides. We shall test our hypothesis that C3d, covalently bound to the pneumococcal surface as a result of opsonization, serves as an immunogenic ligand for the C3d receptor on the B lymphocyte. Our preliminary studies in a serum-free culture system may lead to the development of more broadly immunogenic polysaccharide vaccines. By focusing on the molecular mechanisms of C3 deposition and degradation on the surface of virulent pneumococci, we hope to elucidate the biochemical principles by which surface-bound C3 ligands interact with cellular receptors to direct phagocytic and immunogenic responses of the normal host.